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. 2023 Sep 7;28(9):771-779.
doi: 10.1093/oncolo/oyad082.

BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors

Raphael Colle  1   2   3 , Sara Lonardi  4 , Marine Cachanado  3 , Michael J Overman  5 , Elena Elez  6 , Marwan Fakih  7 , Francesca Corti  8 , Priya Jayachandran  9 , Magali Svrcek  2   10 , Antoine Dardenne  1 , Baptiste Cervantes  1 , Alex Duval  2   3 , Romain Cohen  1   2   3 , Filippo Pietrantonio  8 , Thierry André  1   2   3
Affiliations

BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors

Raphael Colle et al. Oncologist. .

Abstract

Background: We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS).

Patients and methods: Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events.

Results: Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity.

Conclusion: In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

Keywords: BRAF mutation; RAS mutation; Lynch syndrome; deficient mismatch repair; immune checkpoint inhibitors; metastatic colorectal cancer.

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Conflict of interest statement

Sara Lonardi reported research funding (to Institution) from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, and Servier, personal honoraria as invited speaker from Amgen, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, and Servier, and participation in advisory board for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Incyte, Lilly, Merck Serono, MSD, and Servier. Marwan Fakih reported consulting or advisory role for AstraZeneca, Bayer Corporation, Bristol Myers Squibb, Eisai Oncology, Incyte Corporation, Merck, Mirati Therapeutics, Inc., Nouscom, PsiOxus, Roche/Genentech, Taiho Oncology, and Xenthera, and research grants (to Institution) from Bristol Myers Squibb, Genentech, and Verastem. Magali Svrcek reported consulting or advisory role for Astellas Pharma, Bristol-Myers Squibb, MSD Oncology, and Sanofi, and travel, accommodations, expenses from Bristol-Myers Squibb and Ventana Medical Systems. Romain Cohen reported honoraria from Bristol-Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, consulting or advisory role from MSD Oncology, Exeliome Biosciences, and Enterome, research funding from Servier, and travel, accommodations, expenses from MSD Oncology, Bristol-Myers Squibb, and Mylan. Thierry André reported attending advisory board meetings and receiving consulting fees from AstraZeneca, Astellas, Bristol Myers Squibb, Gritstone Oncology, GamaMabs Pharma Sa, GlaxoSmithKline, Merck & Co. Inc., Nordic Pharma, Pierre Fabre, Seagen, Servier, and Transgène, honoraria from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Pierre Fabre, Roche/Ventana, and Servier, and support for meetings from Bristol Myers Squibb, Merck & Co. Inc., and Servier. The other authors indicated no financial relationships.

Figures

Figure 1.
Figure 1.
The algorithm for the Lynch syndrome classification according to the order of execution of MSI PCR test and MMR IHC test. IHC, immunohistochemistry; MMR, mismatch repair gene; MSI-H, microsatellite instability-high; PCR, polymerase chain reaction.
Figure 2.
Figure 2.
Flow chart of the study with reasons for Lynch and sporadic indeterminations in excluded patients.
Figure 3.
Figure 3.
Progression-free survival (PFS) in patients with determined Lynch syndrome and with sporadic MSI-H/dMMR CRC.
See this image and copyright information in PMC

References

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